The goal of this ongoing project is to continue the development of fetal cardiac surgery. Certain congenital heart defects are uncorrectable after birth and there is a clear advantage for intrauterine corrective surgery. This approach requires and understanding of the physiological effects of surgical intervention and extracorporeal circulation on the fetus. Our work in this area to date has allowed us to gain a substantial but incomplete understanding of these issues. The three major pathophysiological responses which limit fetal survival following intervention and extracorporeal circulation (which we identified in the original grant proposal) include: 1. The loss of fetal cardiovascular homeostasis in the pre-bypass phase of fetal intervention. 2. The "step- function" rise in fetal vascular resistance at the institution of fetal bypass which is associated with acute decompensation. 3. The gradual rise in placental vascular resistance during and after fetal bypass which results in depressed placental blood flow. The specific focus of this project remains as stated in the original proposal, to identify the mediators and detailed pathophysiologic mechanisms of these three responses with an eye towards clinical application of this information to advance the development of human fetal cardiac surgery. Each of the three responses will be systematically evaluated. Experiments examining the pre-bypass problem will focus on the role of the fetal stress response. Further understanding of this response in presently limited by our fetal animal (sheep) and by the methodology of measuring the fetal cardiac response to stress. We propose to study the efficacy of narcotic anesthesia in blunting the stress response in an instrumented primate model. Additionally load independent measurements of cardiac function (the conductance catheter technique) will be applied in this model in order to directly measure myocardial functional response to stress. Experiments addressing the "step function " rise in fetal vascular resistances will examine the inhibition of this response using specifically designed bypass circuitry. Our methodology will include ultrasonic flow transducers to continuously measure instantaneous changes in organ flow in addition to our more specific miscrosphere techniques which do not have this capability. In recognition of the multiple factors affecting the placental vasculature, experiments addressing the gradual rise in post bypass placental resistance will examine the role of placental vascular endothelial injury in addition to the role of eicosanoids. Using the information and techniques which have been developed in the course of these studies we will then examine the fetal hemodynamics, oxygen consumption, and metabolic changes in the post bypass period. Finally the long term outcome (survival, ventricular function, and organ pathology) following fetal bypass will be studied.